1,2,4-Diazaphosphole nucleosides. Synthesis, structure, and antitumor activity of nucleosides with a lambda 3 phosphorus atom

J Med Chem. 1990 Feb;33(2):572-6. doi: 10.1021/jm00164a016.

Abstract

Glycosylation of 1,2,4 lambda 3-diazaphosphole (4) under Lewis acid catalyzed conditions gave 1-alpha-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole (5) as the only product. Ethyl 1,2,4 lambda 3-diazaphosphole-3-carboxylate (10) was synthesized by the cyclocondensation of ethyl (chlorophosphinidene)(trimethylsilyl)acetate (8) with (trimethylsilyl)diazomethane and subsequent desilylation with tetra-n-butylammonium fluoride. Reaction of 10 with methanolic ammonia at 80 degrees C gave 1,2,4 lambda 3-diazaphosphole-3-carboxamide. Glycosylation of 10 using trimethylsilyl triflate catalyst followed by ammonlysis gave the ribavirin (1) analogue 1-beta-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole-3-carboxamide (11). Acetylation of 11 and subsequent treatment with phosphorus pentasulfide gave 2',3',5'-tri-O-acetyl-1-beta-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole-3- thiocarboxamide (13). Deprotection with methanolic ammonia gave 1-beta-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole-3-thiocarboxamide (14). Compound 14 gave a 25% increase in life span (ILS) against L1210 in female BDF1 mice. The anomeric configuration and site of glycosylation of 5 and 13 were established by single-crystal X-ray crystallography.

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / therapeutic use
  • Azides / adverse effects
  • Azides / chemical synthesis*
  • Azides / therapeutic use
  • Chemical Phenomena
  • Chemistry
  • IMP Dehydrogenase / antagonists & inhibitors
  • Mice
  • Models, Molecular
  • Neoplasms, Experimental / drug therapy
  • Nucleosides / chemical synthesis*
  • Organophosphorus Compounds / adverse effects
  • Organophosphorus Compounds / chemical synthesis*
  • Organophosphorus Compounds / therapeutic use
  • Structure-Activity Relationship
  • Survival Analysis
  • X-Ray Diffraction

Substances

  • Antineoplastic Agents
  • Azides
  • Nucleosides
  • Organophosphorus Compounds
  • IMP Dehydrogenase